Abnormalities in brain function contribute to dependence on drugs of abuse. This project aims to identify these abnormalities, and to offer leads in developing new treatment modalities. In a study using positron emission tomography (PET), the presentation of drug-related, but not neutral, visual stimuli induced drug craving and increased glucose metabolism in cortical and limbic areas in cocaine users but not in normal control subjects. Correlations of metabolic increases in dorsolateral prefrontal cortex, medial temporal lobe, and cerebellum with reports of craving suggest that environmental stimuli related to past cocaine use activate components of a neural network, which integrates emotional and cognitive aspects of memory, thereby linking craving to stimuli. Extensions of this study will address whether craving for other drugs involves the same brain regions that have been linked to cocaine craving. A structural imaging study, using volumetric magnetic resonance imaging (MRI) analysis, demonstrated that the prefrontal lobe is smaller in abstinent polydrug abusers than in controls. This finding suggests that structural deficits contribute to the neuropathological basis for functional impairment in these areas, as demonstrated by PET and cognitive studies of substance abusers. Human immunodeficiency virus (HIV)-induced infection can be associated with cognitive deficits. We observed altered brain glucose metabolism in subcortical and limbic structures in a group of AIDS patients compared with controls matched for lifestyle and other demographic factors, and in a case study, we noted amelioration of metabolic abnormalities by peptide T. Other research efforts are directed at improving PET technology. A newly developed mathematical model greatly reduces the arterial blood sampling requirements for the PET [18F]fluorodeoxyglucose, and we are proceeding toward further simplification by incorporating the use of venous samples and dynamic data analysis. In the area of radiotracer development, we have focused on developing new radioligands for nicotine acetylcholine receptors (nAChRs) in the brain. We have synthesized several new radiolabeled analogues of the nicotinic agonist epibatidine that have high affinity and the requisite pharmacological selectivity. (+/-)-Exo-2- (2-[18F]fluoro-5-pyridyl-7-azabiocyclo[2.2.1]- heptane, one the more promising radioligands, is being evaluated in animal studies.